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Childhood Cancer-Linked Mutations May Point Toward New Targets

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The discovery of mutations in two related genes that are involved in neuroblastoma, the most aggressive form of childhood cancer, may identify a novel, defective pathway in these cancers and help uncover potential new therapeutic targets. Neuroblastoma tumors of the peripheral nervous system are the most common solid tumor that occurs in children, accounting for 7 percent of all childhood cancers, but 10 to 15 percent of all childhood cancer-related deaths.

Michael D. Hogarty, M.D., a pediatric oncologist at The Children’s Hospital of Philadelphia along with Victor Velculescu, M.D., Ph.D., of the Johns Hopkins Kimmel Cancer Center, and their colleagues identified alterations in two genes, ARID1A and ARID1B, in genome sequencing 74 neuroblastomas in 71 children. Neither gene had previously been reported as involved in neuroblastoma. The investigators reported their findings in the online edition of Nature Genetics on Dec. 2, 2012.

In studying 74 tumors from 71 patients, 71 tumors were analyzed for both rearrangements and base-pair changes. Cancer-specific mutations were found in a variety of genes previously linked to neuroblastoma, including the ALK and MYCN genes.

But in tumors from 8 of the 71 (11%) patients, the investigators found alterations in the ARID1A and ARID1B genes, which normally control the way DNA folds to allow or block protein production.

The children with ARID1A or ARID1B mutations had far worse survival on average than those without the genetic alterations—386 days compared with 1,689 days. All but one of these patients died of progressive disease, including one child whose neuroblastoma was thought to be highly curable.

The two mutation-carrying genes are thought to affect chromatin, a combination of DNA and protein that regulates the activities of genes and ultimately controls the behavior of a cell. During normal development, neural cells switch from a primitive, rapidly dividing state (neuroblasts) into a more differentiated, or mature state (neurons).

Dr. Hogarty said that mutations in these two genes may prevent this orderly transition, keeping the neural cells in the uncontrolled stage of growth that progresses to cancer. “Unfortunately,” he said, “Children with these mutations have a particularly aggressive, treatment-resistant form of neuroblastoma.”

The scientists further reported that they had developed a method to identify rearranged DNA fragments in sera, providing, they said, personalized biomarkers for minimal residual disease detection and monitoring. The results, they concluded, highlight the dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of patients with neuroblastoma.

“All tumors harbor genetic mistakes that leave a fingerprint in the DNA, and tumor DNA is often detected in the blood as well,” Dr. Hogarty explained. “We may be able to develop a blood test personalized to each cancer patient to detect their tumor fingerprint in circulating blood DNA. This would permit oncologists to more accurately monitor patients for treatment response and recurrence, and offer a tool to help guide treatment decisions.”

He further commented that, “When this project started, it was the first of its kind to focus on a childhood tumor. This is important because cataloging all the DNA mutations in neuroblastoma, or any tumor, will allow us to better understand the enemy, and ultimately to make better treatment decisions.”

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